The present invention relates to a process for preparing fluorine-containing benzaldehydes by reduction of the corresponding aromatic acid chlorides.
Fluorinated benzaldehydes are important building blocks for active compounds in the pharmaceuticals sector. They can also be converted by reduction into the corresponding benzyl alcohols that likewise have a wide range of uses for active compounds in the pharmaceuticals sector.
Processes for preparing fluorine-containing benzaldehydes are known. Thus, fluorinated benzoyl chlorides are reduced to the corresponding benzaldehydes by a Rosenmund reaction (see Org. React. Vol. 4, 362) in sulfolane as solvent (EP-A 171 065). High yields are obtained in this way, but the use of a solvent means that the process has the disadvantage of a lower space-time yield and higher materials costs. Furthermore, especially for 3,5-bis(trifluoromethyl)benzoyl chloride, increased overhydrogenation of the benzoyl chloride to the corresponding benzene is observed.
Specifically for the preparation of 3,5-bis(trifluoromethyl)benzaldehyde, there are many known synthetic routes that are not all suitable for a preparation on a relatively large scale. Thus, the corresponding bromobenzene has been reacted with butyllithium and N,N-dimethyl-formamide (J. Med. Chem. 16, 1399 (1973) and Chem. Ber. 129, 233 (1996)). Due to the handling of pyrophoric organolithium compounds, this process has particularly high safety requirements.
The Grignard reaction of the corresponding bromobenzene with magnesium and triethyl orthoformate (Eur. J. Med. Chem. Chim. Ther. 14, 411 (1979)) has similarly high safety requirements for the handling of organomagnesium compounds.
The industrially difficult-to-obtain 3,5-bis(trifluoromethyl)benzyl alcohol has also been oxidized with pyridinium dichromate in moderate yield (J. Amer. Chem. Soc. 107, 2442 (1985)). This produces toxic chromium-containing waste that requires costly disposal.
A Stephen reduction of the corresponding nitrile using tin(II) chloride/hydrogen chloride gas (J. Chem. Soc. Perkin Trans. 2, 1987, 639) gives stoichiometric amounts of toxic tin salts as waste product.
Reduction of benzoyl chloride by means of tri-tert-butoxy-lithium-aluminum hydride in diglyme has also been described (J. Med. Chem. 15, 775 (1972)). However, aluminum hydrides can attack trifluoromethyl groups. A further disadvantage is the formation of stoichiometric amounts of aluminum salts that must be disposed of.
We have now found a process for preparing fluorine-containing benzaldehydes of the formula 
wherein
n represents 1 or 2, and
R1, R2, and R3 each represent, independently of one another, hydrogen, fluorine, chlorine, bromine, C1-C6-alkyl, C1-C6-fluoroalkyl, C1-C6-fluoroalkoxy, or C1-C6-fluoroalkylthio, where at least one of the radicals R1 to R3 represents fluorine or a fluorine-containing radical and not more than two of the radicals R1 to R3 represents bromine, C1-C6-fluoroalkoxy, and/or C1-C6-fluoroalkylthio,
comprising reacting an aromatic acid chloride of the formula 
where R1, R2, R3, and n are as defined for formula (I), with hydrogen in the presence of a supported palladium catalyst and a catalyst moderator.
If the radicals R1 to R3 are C1-C6-fluoroalkyl, C1-C6-fluoroalkoxy, or C1-C6-fluoroalkylthio, they can be monofluorinated, polyfluorinated, or perfluorinated C1-C6-alkylthio, C1-C6-alkoxythio, or C1-C6-fluoroalkylthio radicals.
The radicals R1 to R3 preferably each represent, independently of one another, H, F, Cl, Br, CH3, C2H5, CF3, CF2CH3, C2F5, OCF3, or SCF3, where at least one of the radicals R1 to R4 represents F, CF3, CF2CH3, C2F5, OCF3, or SCF3 and not more than one of the radicals R1 to R4 represents bromine, OCF3, or SCF3.
If the radicals R1 to R3 are different from hydrogen and only one COCI group is present, they are preferably located in the 3, 4, and 5 position(s) of the benzene ring relative to the COCI group.
Particular preference is given to using mono-, di-, and trifluoro-benzoyl chlorides, mono- and bis-trifluoromethylbenzoyl chlorides, monotrifluoromethoxybenzoyl chlorides, and monochloro- and monobromotrifluoromethylbenzoyl chlorides in the process of the invention for preparing the corresponding fluorine-containing benzaldehydes.
The hydrogen can be employed, for example, at pressures in the range from 0.5 to 3 bar. It is preferably employed under atmospheric pressure. The hydrogen gas can be passed into the reaction mixture by means of, for example, a tube or a frit. The hydrogen gas can also be passed into the space above the mixture. The hydrogen gas is preferably passed into the reaction mixture.
Suitalble support materials for the supported palladium catalyst are, for example, carbon, aluminum oxides, silicates, silica, and barium sulfate. Preference is given to carbon and barium sulfate. The supported palladium catalysts can contain, for example, from 1 to 10% by weight of palladium. The weight ratio of supported palladium catalyst to the aromatic acid chloride used can be, for example, from 1:2 to 1:1000 (preferably from 1:5 to 1:500).
Suitable catalyst moderators are, for example, organic sulfur compounds. Preference is given to thiophenol, thioanisole, thiourea, sulfolane, and quinoline-sulfur complexes. Particular preference is given to quinoline-sulfur complexes as described, for example, in Org. Reactions, Vol. 4, 362, or can be obtained as described in the present Example 1 or by methods analogous thereto.
The weight ratio of catalyst moderator to supported palladium catalyst can be, for example, from 1:1 to 1:500 (preferably from 1:10 to 1:200).
The catalyst moderator can, for example, be initially charged together with the aromatic acid chloride and the catalyst. It is also possible for the supported palladium catalyst to be brought into contact with the catalyst moderator first, optionally in the presence of an auxiliary, and for the catalyst/moderator combination then to be used in the process of the invention.
After the reaction is complete, the catalyst can be separated off, e.g., by filtration, and reused in the next batch. This reuse can be repeated up to 5 or more times. Reused catalysts can generally be used without further addition of catalyst moderator.
The auxiliary can be, for example, a small amount of an aromatic hydrocarbon, a halogenated hydrocarbon, a halogenoaromatic, an aprotic amide, an acyclic or cyclic ether, or a sulfone. For the purposes of the present invention, the term xe2x80x9ca small amountxe2x80x9d is, for example, an amount of up to 2.5 ml per 100 g (preferably from 0.02 to 0.5 ml per 100 g) of aromatic acid chloride used.
The auxiliary can not only serve to improve contact between the supported palladium catalyst and the catalyst moderator, but also, for example, for slurrying a supported palladium catalyst already containing catalyst moderator before the addition of the aromatic acid chloride.
The reaction of the invention is carried out at temperatures at which the starting material is liquid, for example, at temperatures in the range from 20 to 200xc2x0 C. If a starting material has a melting point above 2020  C., the melting point of the starting material is the lowest suitable reaction temperature. If a starting material boils at below 200xc2x0 C. under atmospheric pressure, the reaction may be carried out under superatmospheric pressure so that the starting material remains in the liquid state. It is also advantageous to carry out the reaction of the invention at temperatures and pressures at which the respective product is liquid. In general, the reaction can be carried out at temperatures in the range from 70 to 130xc2x0 C. at atmospheric pressure. Particularly preferred reaction temperatures are in the range from 80 to 120xc2x0 C.
The reaction of the invention can be carried out, for example, by initially charging an aromatic acid chloride, a supported palladium catalyst containing a catalyst moderator, and optionally a small amount of auxiliary and setting the reaction conditions while introducing hydrogen. It is also possible for an aromatic acid chloride, a supported palladium catalyst, a catalyst moderator, and optionally a small amount of auxiliary to be initially charged and the reaction conditions to be set while introducing hydrogen.
The reaction is complete when the offgases from the reaction no longer have an acidic reaction. The workup of the reaction mixture, optionally after cooling and depressurization, can be carried out in various ways, for example, by distilling the fluorine-containing benzaldehyde prepared directly from the reaction mixture, optionally under reduced pressure.
It is also possible for the catalyst to be separated off first, e.g., by filtration, and the product then to be isolated from the filtrate by distillation, optionally under reduced pressure. In this case, a small amount of over-hydrogenated product (i.e., benzene derivative) and/or a small amount of any auxiliary used may be obtained as first fraction.
It is frequently also possible for the crude product obtained after separating off the catalyst to be used further as such, e.g., for preparing fluorinated benzyl alcohols by reduction.
The process of the invention makes it possible to prepare fluorinated benzaldehydes of the formula (I) in higher space-time yields, without solvent and with less overhydrogenation to the benzene stage than hitherto, with no toxic waste being obtained and no particular safety measures being necessary.